Specific Aim 1 is to dissect the genetic factors contributing to plasma lipoprotein metabolism in the mouse model. The approach has been to map candidate genes involved in plasma lipoprotein metabolism and to identify quantitative trait loci (QTLs) associated with plasma lipoprotein variations and obesity. In cases where candidate genes coincide with quantitative loci, we will look for variations in sequence or expression of the candidate gene. In selected cases, we will further characterize the QTL by isolating the responsible gene as a congenic mouse strain. In aims 2 and 3, we carry out detailed characterization of loci with important effects on lipid metabolism. Specific Aim 2 will characterize and identify a novel gene, Hyplip1, that causes combined hyperlipidemia in the mouse model. We will biochemically characterize the effects of the Hylip1 gene and perform fine-structure genetic mapping. A particularly exciting aspect of the Hyplip1 locus is its synteny to the QTL, for human familial combined hyperlipidemia studied in Project V. In order to better focus the efforts of both projects on this exciting region; positional cloning of the Hypli1 gene will be carried out in collaboration with Project V. Specific Aim 3 will determine the mechanism by which apolipoprotein AII influences triglyceride metabolism, particularly the insulin resistance phenotype we observe in apolipoprotein AII transgenic mice. Since these mice exhibit increased plasma levels of triglycerides and free fatty acids, as well as increased fat pad mass and insulin resistance, we have begun to investigate the effect of the transgene on adipocyte metabolism. Strikingly, we found that HDL from control mice can simulate hydrolysis of triglycerides from adipose tissue through a direct effect on adipocytes, a pathway not previously identified. By contrast, HDL from apolipoprotein AII transgenic mice, presumably enriched in apolipoprotein AII, has lost this ability. As part of this aim, we will examine the pathway by which HDL affects lipolysis in adipocytes.